Structural insights into human acid-sensing ion channel 1a inhibition by snake toxin mambalgin1
Demeng Sun,
Sanling Liu,
Siyu Li,
Mengge Zhang,
Fan Yang,
Ming Wen,
Pan Shi,
Tao Wang,
Man Pan,
Shenghai Chang,
Xing Zhang,
Longhua Zhang,
Changlin Tian,
Lei Liu
Affiliations
Demeng Sun
Hefei National Laboratory of Physical Sciences at Microscale, Anhui Laboratory of Advanced Photonic Science and Technology and School of Life Sciences, University of Science and Technology of China, Hefei, China; Tsinghua-Peking Joint Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, China
Sanling Liu
Hefei National Laboratory of Physical Sciences at Microscale, Anhui Laboratory of Advanced Photonic Science and Technology and School of Life Sciences, University of Science and Technology of China, Hefei, China
Siyu Li
Hefei National Laboratory of Physical Sciences at Microscale, Anhui Laboratory of Advanced Photonic Science and Technology and School of Life Sciences, University of Science and Technology of China, Hefei, China
Mengge Zhang
Hefei National Laboratory of Physical Sciences at Microscale, Anhui Laboratory of Advanced Photonic Science and Technology and School of Life Sciences, University of Science and Technology of China, Hefei, China
Fan Yang
Hefei National Laboratory of Physical Sciences at Microscale, Anhui Laboratory of Advanced Photonic Science and Technology and School of Life Sciences, University of Science and Technology of China, Hefei, China
Ming Wen
Hefei National Laboratory of Physical Sciences at Microscale, Anhui Laboratory of Advanced Photonic Science and Technology and School of Life Sciences, University of Science and Technology of China, Hefei, China
Pan Shi
Hefei National Laboratory of Physical Sciences at Microscale, Anhui Laboratory of Advanced Photonic Science and Technology and School of Life Sciences, University of Science and Technology of China, Hefei, China
Tao Wang
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, China
Man Pan
Tsinghua-Peking Joint Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, China
Shenghai Chang
School of Medicine, Zhejiang University, Hangzhou, China
Xing Zhang
School of Medicine, Zhejiang University, Hangzhou, China
Longhua Zhang
Hefei National Laboratory of Physical Sciences at Microscale, Anhui Laboratory of Advanced Photonic Science and Technology and School of Life Sciences, University of Science and Technology of China, Hefei, China
Hefei National Laboratory of Physical Sciences at Microscale, Anhui Laboratory of Advanced Photonic Science and Technology and School of Life Sciences, University of Science and Technology of China, Hefei, China; High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, China
Lei Liu
Tsinghua-Peking Joint Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, China
Acid-sensing ion channels (ASICs) are proton-gated cation channels that are involved in diverse neuronal processes including pain sensing. The peptide toxin Mambalgin1 (Mamba1) from black mamba snake venom can reversibly inhibit the conductance of ASICs, causing an analgesic effect. However, the detailed mechanism by which Mamba1 inhibits ASIC1s, especially how Mamba1 binding to the extracellular domain affects the conformational changes of the transmembrane domain of ASICs remains elusive. Here, we present single-particle cryo-EM structures of human ASIC1a (hASIC1a) and the hASIC1a-Mamba1 complex at resolutions of 3.56 and 3.90 Å, respectively. The structures revealed the inhibited conformation of hASIC1a upon Mamba1 binding. The combination of the structural and physiological data indicates that Mamba1 preferentially binds hASIC1a in a closed state and reduces the proton sensitivity of the channel, representing a closed-state trapping mechanism.
